Chronic hepatitis C virus (HCV) infection is an important and growing cause of morbidity and mortality in the United States. In particular, a disproportionate burden of mortality is borne by groups with specific disease susceptibilities. These include patients with HIV coinfection and patients with coexistent fatty liver and insulin resistance, whose natural history of disease progression is significantly accelerated. The basis for these observations is not well understood. In addition, these special groups also appear to respond less well to interferon (IFN)-based antiviral therapy than patients with competent immune systems. This proposal will demonstrate the candidate's track record of research productivity and lengthy commitment to patient oriented research in hepatitis C virus and his impressive record of mentorship in the development of junior faculty and fellows embarking on clinical and translational research careers in liver disease. The intellectual focus of the candidate's program will be to understand the basis for the accelerated natural history and limited antiviral response rate of HCV disease in special populations. Particular attention will be devoted to study of mechanisms of disease in HCV-HIV coinfection, a major program of investigation at our institution. Another of our important areas of study is the relationship between HCV and increased insulin resistance. This K24 proposal will free Dr. Chung from enough clinical responsibilities to allow him to provide more intensive and focused mentoring and accomplishment of the following Aims: (1) Mentor fellows and junior faculty in initiation of patient-oriented research careers in the study of HCV- related disease in special populations, predominantly in (a) HCV and HIV coinfection and (b) the relationship between HCV and insulin resistance (2) Initiate innovative pilot clinical trials in difficult to treat HCV-related liver disease based on key observations from our mechanistic work. These will include (a) a pilot trial of thiazolidinediones to improve response to PEG-IFN and ribavirin in HCV-HIV-infected prior nonresponders who have insulin resistance;and (b) a pilot trial in HCV-infected patients of HMG CoA-reductase inhibitors, which have shown antiviral activity against HCV in cell-based models in our and others'laboratories. By providing increased mentoring to fellows and junior faculty in translational research in liver diseases, Dr. Chung will be able to devote more time to the goal expanding research capability in this critical area of patient-oriented investigation. By developing investigators committed to patient-oriented research, Dr. Chung has strong confidence that they will follow suit in mentoring their own fellows and faculty, in so doing creating a highly desirable multiplier effect.